The invention relates to a pharmaceutical liposomal composition comprising 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno [2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl) propanoic acid, referred to herein as ‘Compound A’, or a pharmaceutically acceptable salt thereof. More specifically the invention relates to a liposomal vehicle, an organic concentrate composition comprising Compound A, and a pharmaceutical composition for parenteral administration comprising liposomes and Compound A. Furthermore, the invention relates to the use of such compositions for the treatment of cancer. ‘Compound A’ as used herein includes all enantiomers, diastereoisomers, and atropisomers thereof, or mixtures thereof, and also optionally includes the pharmaceutically acceptable salts thereof.
The structure of Compound A is

2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid.
In a particular embodiment, Compound A is:

(2R)-2-{[(5Sa)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid. In a further embodiment, Compound A used in the composition described herein is the free molecule (not a salt thereof).
The preparation of Compound A, its use as a Mcl-1 inhibitor for the treatment of cancer and pharmaceutical formulations thereof, are described in WO 2015/097123, the content of which is incorporated by reference. The preparation is specifically disclosed in Example 30 of WO 2015/097123.
Compound A is optically active, having one chiral center and chiral axis. It has limited aqueous solubility across all pHs, including physiologically relevant pHs. In order to enable safe and effective administration of Compound A, and to elicit the required therapeutic effects, Compound A needs to be solubilized.
There are different ways to solubilize poorly soluble compounds for parenteral administration. Typical approaches are the optimization of the pH or the use of co-solvents (e.g. PEG300, PEG400, propylene glycol, or ethanol). If these approaches are, for any reason, not feasible, the use of surfactants may be considered (e.g. Tween® 80 or Cremophor EL®). However, these types of surfactants are frequently associated with adverse effects. Cyclodextrins are established as safe solubilizing agents, yet with limitations as they are not effective solubilizers for all compounds. Moreover, compounds with a high solubility in natural oils (e.g. Propofol) may be solubilized in parenteral fat emulsions.
Another possibility to solubilize poorly soluble compounds is the use of phospholipids (van Hoogevest P., Xiangli L., and Alfred F. “Drug delivery strategies for poorly water-soluble drugs: the industrial perspective” Expert Opinion on Drug Delivery 2011, 8(11), 1481-1500). Thus, phospholipids present themselves as one additional tool for solubilizing poorly soluble compound besides the usual approaches. However, the solubilization of a certain poorly soluble compound by phospholipids cannot be predicted.
The aim of the current invention is to provide a composition which can conveniently be used to solubilize and parenterally deliver Compound A. In particular, there is a need to provide a pharmaceutical composition for Compound A which is safe and efficacious. Further aims are to provide a composition which is stable in the relevant conditions and containers, and which enables administration of an appropriate dose of Compound A over a reasonable timescale. In a further aim, the composition should be able to be manufactured by a reliable and robust process.